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Molecular and Cellular Biology, August 1999, p. 5759-5767, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 Engages the Tumor Necrosis Factor Receptor-Associated Proteins TRADD and Receptor-Interacting Protein (RIP) but Does Not Induce Apoptosis or Require RIP for NF-kappa B Activation

Kenneth M. Izumi,1 Ellen Cahir McFarland,1 Adrian T. Ting,2 Elisabeth A. Riley,1,dagger Brian Seed,2 and Elliott D. Kieff1,*

Department of Medicine, Brigham and Women's Hospital, and Channing Laboratories, Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115-5804,1 and Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 021142

Received 1 December 1998/Returned for modification 11 February 1999/Accepted 29 April 1999

A site in the Epstein-Barr virus (EBV) transforming protein LMP1 that constitutively associates with the tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein TRADD to mediate NF-kappa B and c-Jun N-terminal kinase activation is critical for long-term lymphoblastoid cell proliferation. We now find that LMP1 signaling through TRADD differs from TNFR1 signaling through TRADD. LMP1 needs only 11 amino acids to activate NF-kappa B or synergize with TRADD in NF-kappa B activation, while TNFR1 requires ~70 residues. Further, LMP1 does not require TRADD residues 294 to 312 for NF-kappa B activation, while TNFR1 requires TRADD residues 296 to 302. LMP1 is partially blocked for NF-kappa B activation by a TRADD mutant consisting of residues 122 to 293. Unlike TNFR1, LMP1 can interact directly with receptor-interacting protein (RIP) and stably associates with RIP in EBV-transformed lymphoblastoid cell lines. Surprisingly, LMP1 does not require RIP for NF-kappa B activation. Despite constitutive association with TRADD or RIP, LMP1 does not induce apoptosis in EBV-negative Burkitt lymphoma or human embryonic kidney 293 cells. These results add a different perspective to the molecular interactions through which LMP1, TRADD, and RIP participate in B-lymphocyte activation and growth.

* Corresponding author. Mailing address: Brigham and Women's Hospital, Harvard Medical School, Channing Laboratories, 181 Longwood Ave., Boston, MA 02115-5804. Phone: (617) 525-4252. Fax: (617) 525-4251. E-mail: ekieff{at}rics.bwh.harvard.edu.

dagger Present address: Integrated DNA Technologies, Inc., Brookline, MA 02446.

Molecular and Cellular Biology, August 1999, p. 5759-5767, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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